Aging is characterized by progressive, degenerative changes in many organ systems. Reproductive aging is an early and striking example of these changes that results in birth defects and infertility in women. Age-related degeneration of somatic tissues is a major contributor to disability and death. Treatments that extend human health span and life span are desirable, but no drugs that delay normal age-related degeneration are available. It is a high priority to develop new therapeutic approaches. The long-term objectives of this proposal are to identify drugs that delay age-related degeneration and define the role of adult stem cells in germ line aging. The results will have an important impact by elucidating mechanisms that control aging and suggesting new therapeutic strategies for age-related degenerative changes. We used the powerful C. elegans model system to discover FDA-approved drugs and nutrients that can extend the life span of worms. We analyzed reproductive aging in C. elegans and identified drugs and genes that can extend reproduction. The C. elegans germ line contains a population of adult stem cells, and we demonstrated that this cell population displays age-related decline, establishing C. elegans as a model of stem cell aging. Studies conducted during the previous project period support three innovative hypotheses. (1) Captopril, yohimbine, nicotinic acid, and imipramine act on endogenous processes that control longevity. The life span extension caused by captopril may be mediated by the acn-1 gene. (2) A combination of drugs that act by different mechanisms can cause an additive life span extension. (3) An age-related decline of germ line stem cell function contributes to reproductive aging, and an age-related decline in the Notch signaling pathway may control this decline. To test these hypotheses, we propose two specific aims. Aim 1: Characterize the mechanism of action of compounds that extend the adult life span of worms, including captopril, yohimbine, nicotinic acid and imipramine. This can identify endogenous pathways that modulate longevity and establish the foundation for evaluating therapeutic uses of these compounds. Determine if combinations of different drugs produce an additive life span extension. Prioritize drugs based on mechanism of action, and analyze high priority drugs for the ability to extend the life span of mice. Aim 2: Test the hypothesis that age-related declines i germ line stem cells contribute to reproductive aging. We will establish the time course of age- related changes in germ line stem cells in wild-type animals and use genetics to analyze the role of Notch signaling. Characterize genes and drugs that mediate reproductive aging, including new genes identified in a forward genetic screen for delayed reproductive aging. By combining molecular and genetic approaches, these studies will elucidate mechanisms of aging, advance the field of aging pharmacology and address important gaps in the current understanding of reproductive aging. Importantly, these studies will establish new therapeutic strategies for addressing age-related degenerative changes in humans.